Novel pyridine derivatives as sphingosine 1-phosphate (s1p) receptor modulators

ABSTRACT

The present invention relates to novel pyridine derivatives, processes for preparing them, pharmaceutical compositions containing them and their use as pharmaceuticals as modulators of sphingosine-1-phosphate receptors.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a Divisional application of U.S. patent applicationSer. No. 13/294,604, filed Nov. 11, 2011, which claims the benefit ofU.S. Provisional Application Ser. No. 61/419,276 filed Dec. 3, 2010,both of which are hereby incorporated by reference in their entirety.

FIELD OF THE INVENTION

The present invention relates to novel pyridine derivatives, processesfor preparing them, pharmaceutical compositions containing them andtheir use as pharmaceuticals, as modulators of sphingosine-1-phosphatereceptors. The invention relates specifically to the use of thesecompounds and their pharmaceutical compositions to treat disordersassociated with sphingosine-1-phosphate (S1P) receptor modulation.

BACKGROUND OF THE INVENTION

Sphingosine-1 phosphate is stored in relatively high concentrations inhuman platelets, which lack the enzymes responsible for its catabolism,and it is released into the blood stream upon activation ofphysiological stimuli, such as growth factors, cytokines, and receptoragonists and antigens. It may also have a critical role in plateletaggregation and thrombosis and could aggravate cardiovascular diseases.On the other hand the relatively high concentration of the metabolite inhigh-density lipoproteins (HDL) may have beneficial implications foratherogenesis. For example, there are recent suggestions thatsphingosine-1-phosphate, together with other lysolipids such assphingosylphosphorylcholine and lysosulfatide, are responsible for thebeneficial clinical effects of HDL by stimulating the production of thepotent antiatherogenic signaling molecule nitric oxide by the vascularendothelium. In addition, like lysophosphatidic acid, it is a marker forcertain types of cancer, and there is evidence that its role in celldivision or proliferation may have an influence on the development ofcancers. These are currently topics that are attracting great interestamongst medical researchers, and the potential for therapeuticintervention in sphingosine-1-phosphate metabolism is under activeinvestigation.

SUMMARY OF THE INVENTION

A group of novel pyridine derivatives which are potent and selectivesphingosine-1-phosphate modulators has been discovered. As such, thecompounds described herein are useful in treating a wide variety ofdisorders associated with modulation of sphingosine-1-phosphatereceptors. The term “modulator” as used herein, includes but is notlimited to: receptor agonist, antagonist, inverse agonist, inverseantagonist, partial agonist, partial antagonist.

This invention describes compounds of Formula I, which havesphingosine-1-phosphate receptor biological activity. The compounds inaccordance with the present invention are thus of use in medicine, forexample in the treatment of humans with diseases and conditions that arealleviated by S1P modulation.

In one aspect, the invention provides a compound having Formula I or apharmaceutically acceptable salt thereof or stereoisomeric formsthereof, or the geometrical isomers, enantiomers, diastereoisomers,tautomers, zwitterions and pharmaceutically acceptable salts thereof:

wherein:

A is C₆₋₁₀ aryl, heterocycle, C₃₋₈ cycloalkyl or C₃₋₈ cycloalkenyl;

B is C₆₋₁₀ aryl, heterocycle, C₃₋₈ cycloalkyl or C₃₋₈ cycloalkenyl;

R¹ is H, halogen, —OC₁₋₈ alkyl, C₁₋₈ alkyl, CN, C(O)R¹¹, NO₂, NR¹²R¹³ orhydroxyl;

R² is H, halogen, —OC₁₋₈ alkyl, C₁₋₈ alkyl, CN, C(O)R¹¹, NO₂, NR¹²R¹³ orhydroxyl;

R³ is H, halogen, —OC₁₋₈ alkyl, C₁₋₈ alkyl, CN, C(O)R¹¹, NO₂, NR¹²R¹³ orhydroxyl;

R⁴ is H, halogen, —OC₁₋₆ alkyl, C₁₋₈ alkyl, CN, C(O)R¹¹, NR¹²R¹³ orhydroxyl;

R⁵ is H, halogen, —OC₁₋₈ alkyl, C₁₋₈ alkyl, CN, C(O)R¹¹, NR¹²R¹³ orhydroxyl;

R⁶ is H, halogen, —OC₁₋₈ alkyl, C₁₋₈ alkyl, CN, C(O)R¹¹, NR¹²R¹³ orhydroxyl;

R⁷ is H, halogen, —OC₁₋₈ alkyl, C₁₋₈ alkyl, CN, C(O)R¹¹, NR¹²R¹³ orhydroxyl;

R⁸ is H, halogen, —OC₁₋₈ alkyl, C₁₋₈ alkyl, CN, C(O)R¹¹, NR¹²R¹³ orhydroxyl;

L is O, S, NH or CH₂;

R¹¹ is H or C₁₋₆ alkyl;

R¹² is H or C₁₋₆ alkyl;

R¹³ is H or C₁₋₆ alkyl;

R¹⁴ is H, C₁₋₆ alkyl or C₃₋₆ cycloalkyl; and

R¹⁵ is H, C₁₋₆ alkyl or C₃₋₆ cycloalkyl.

In another aspect, the invention provides a compound having Formula Iwherein L is CH₂.

In another embodiment, the invention provides a compound having FormulaI wherein:

A is C₆ aryl or heterocycle;

B is C₆ aryl or C₃₋₈ cycloalkyl;

R¹ is H, halogen, —OC₁₋₆ alkyl, C₁₋₆ alkyl or NO₂;

R² is H, halogen, —OC₁₋₆ alkyl, C₁₋₆ alkyl or NO₂;

R³ is H, halogen, —OC₁₋₆ alkyl, C₁₋₆ alkyl or NO₂;

R⁴ is H, halogen or C₁₋₆ alkyl,

R⁵ is H, halogen or C₁₋₆ alkyl;

R⁶ is H, halogen or C₁₋₆ alkyl;

R⁷ is H, halogen or C₁₋₆ alkyl;

R⁸ is H, halogen or —C₁₋₆ alkyl; and

L is CH₂.

In another embodiment, the invention provides a compound having FormulaI wherein:

A is phenyl, thiophene or pyridine;

B is phenyl, cyclohexyl or cyclopentyl;

R¹ is H, chloro, bromo, fluoro, trifluoromethyl, methyl, ethyl, methoxyor —NO₂;

R² is H, chloro, bromo, fluoro, trifluoromethyl, methyl, ethyl, methoxyor —NO₂,

R³ is H, chloro, bromo, fluoro, trifluoromethyl, methyl, ethyl, methoxyor —NO₂;

R⁴ is H, methyl, chloro or iso-butyl;

R⁵ is H, methyl, chloro or iso-butyl;

R⁶ is H, methyl, chloro or iso-butyl;

R⁷ is H;

R⁸ is H; and

L is CH₂.

In another embodiment, the invention provides a compound having FormulaI wherein:

In another embodiment, the invention provides a compound having FormulaI wherein:

In another embodiment, the invention provides a compound having FormulaI wherein:

In another embodiment, the invention provides a compound having FormulaI wherein:

R¹ is H, halogen, —OC₁₋₆ alkyl, C₁₋₆ alkyl, CN, C(O)R¹¹, NO₂, NR¹²R¹³ orhydroxyl;R² is H, halogen, —OC₁₋₆ alkyl, C₁₋₆ alkyl, CN, C(O)R¹¹, NO₂, NR¹²R¹³ orhydroxyl;R³ is H, halogen, —OC₁₋₆ alkyl, C₁₋₆ alkyl, CN, C(O)R¹¹, NO₂, NR¹²R¹³ orhydroxyl;R⁴ is H, halogen, —OC₁₋₆ alkyl, C₁₋₆ alkyl, CN, C(O)R¹¹, NR¹²R¹³ orhydroxyl;R⁵ is H, halogen, —OC₁₋₆ alkyl, C₁₋₆ alkyl, CN, C(O)R¹¹, NR¹²R¹³ orhydroxyl;R⁶ is H, halogen, —OC₁₋₆ alkyl, C₁₋₆ alkyl, CN, C(O)R¹¹, NR¹²R¹³ orhydroxyl;R⁷ is H, halogen, —OC₁₋₆ alkyl, C₁₋₆ alkyl, CN, C(O)R¹¹, NR¹²R¹³ orhydroxyl;R⁸ is H, halogen, —OC₁₋₆ alkyl, C₁₋₆ alkyl, CN, C(O)R¹¹, NR¹²R¹³ orhydroxyl;

L is CH₂;

R¹¹ is H or C₁₋₆ alkyl;R¹² is H or C₁₋₆ alkyl;R¹³ is H or C₁₋₆ alkyl.R¹⁴ is H, C₁₋₆ alkyl or C₃₋₆ cycloalkyl; andR¹⁵ is H, C₁₋₆ alkyl or C₃₋₆ cycloalkyl.

In another embodiment, the invention provides a compound having FormulaI wherein:

R¹ is H, halogen, —OC₁₋₆ alkyl, C₁₋₆ alkyl or NO₂;

R² is H, halogen, —OC₁₋₆ alkyl, C₁₋₆ alkyl or NO₂;

R³ is H, halogen, —OC₁₋₆ alkyl, C₁₋₆ alkyl or NO₂;

R⁴ is H, halogen or C₁₋₆ alkyl,

R⁵ is H, halogen or C₁₋₆ alkyl;

R⁶ is H, halogen or C₁₋₆ alkyl;

R⁷ is H, halogen or C₁₋₆ alkyl;

R⁸ is H, halogen or —C₁₋₆ alkyl;

L is CH₂.

R¹⁴ is H, C₁₋₆ alkyl or C₃₋₆ cycloalkyl; andR¹⁵ is H, C₁₋₆ alkyl or C₃₋₆ cycloalkyl.

In another embodiment, the invention provides a compound having FormulaI wherein:

R¹ is H, chloro, bromo, fluoro, methyl, ethyl, methoxy or —NO₂;

R² is H, chloro, trifluoromethyl, methyl or methoxy;

R³ is H, fluoro or methyl;

R⁴ is H or methyl;

R⁵ is H, methyl, chloro or iso-butyl;

R⁶ is H, methyl or chloro;

R⁷ is H;

R⁸ is H;

L is CH₂;

R¹⁴ is H, C₁₋₆ alkyl or C₃₋₆ cycloalkyl; andR¹⁵ is H, C₁₋₆ alkyl or C₃₋₆ cycloalkyl.

The term “alkyl”, as used herein, refers to saturated, monovalenthydrocarbon moieties having linear or branched moieties or combinationsthereof and containing 1 to 8 carbon atoms. One methylene (—CH₂—) group,of the alkyl can be replaced by oxygen, sulfur, sulfoxide, nitrogen,carbonyl, carboxyl, sulfonyl, or by a divalent C₃₋₆ cycloalkyl. Alkylgroups can be substituted by halogen atoms, hydroxyl, cycloalkyl, amino,non-aromatic heterocycles, carboxylic acid, phosphonic acid groups,sulphonic acid groups, phosphoric acid.

The term “cycloalkyl”, as used herein, refers to a monovalent ordivalent group of 3 to 8 carbon atoms, derived from a saturated cyclichydrocarbon. Cycloalkyl groups can be monocyclic or polycyclic.Cycloalkyl can be substituted by alkyl groups or halogen atoms.

The term “cycloalkenyl”, as used herein, refers to a monovalent ordivalent group of 5 to 8 carbon atoms derived from a saturatedcycloalkyl having one double bond. Cycloalkenyl groups can be monocyclicor polycyclic. Cycloalkenyl groups can be substituted by alkyl groups orhalogen atoms.

The term “halogen”, as used herein, refers to an atom of chlorine,bromine, fluorine, iodine.

The term “alkenyl”, as used herein, refers to a monovalent or divalenthydrocarbon radical having 2 to 6 carbon atoms, derived from a saturatedalkyl, having at least one double bond. C₂₋₆ alkenyl can be in the E orZ configuration. Alkenyl groups can be substituted by alkyl groups.

The term “alkynyl”, as used herein, refers to a monovalent or divalenthydrocarbon radical having 2 to 6 carbon atoms, derived from a saturatedalkyl, having at least one triple bond. Alkynyl groups can besubstituted by alkyl groups.

The term “heterocycle” as used herein, refers to a 3 to 10 memberedring, which can be aromatic or non-aromatic, saturated or non-saturated,containing at least one heteroatom selected form O or N or S orcombinations of at least two thereof, interrupting the carbocyclic ringstructure. The heterocyclic ring can be interrupted by a C═O; the Sheteroatom can be oxidized. Heterocycles can be monocyclic orpolycyclic. Heterocyclic ring moieties can be substituted by hydroxyl,alkyl groups or halogen atoms.

The term “aryl” as used herein, refers to an organic moiety derived froman aromatic hydrocarbon consisting of a ring containing 6 to 10 carbonatoms by removal of one hydrogen. Aryl groups can be monocyclic orpolycyclic. Aryl can be substituted by halogen atoms, —OC₁₋₆ alkyl, C₁₋₆alkyl, 1 CN, —C(O)H or —C(O)(C₁₋₆ alkyl), NH(C₁₋₆ alkyl), NH₂, N(C₁₋₆alkyl)(C₁₋₆ alkyl), NO₂ or hydroxyl groups.

The term “hydroxyl” as used herein, represents a group of formula “—OH”.

The term “carbonyl” as used herein, represents a group of formula“—C(O)”.

The term “carboxyl” as used herein, represents a group of formula“—C(O)O—”.

The term “sulfonyl” as used herein, represents a group of formula“—SO₂”.

The term “sulfate” as used herein, represents a group of formula“—O—S(O)₂—O—”.

The term “carboxylic acid” as used herein, represents a group of formula“—C(O)ON”.

The term “sulfoxide” as used herein, represents a group of formula“—S═O”.

The term “phosphonic acid” as used herein, represents a group of formula“—P(O)(OH)₂”.

The term “phosphoric acid” as used herein, represents a group of formula“—(O)P(O)(OH)₂”.

The term “sulphonic acid” as used herein, represents a group of formula“—S(O)₂OH”.

The formula “H”, as used herein, represents a hydrogen atom.

The formula “O”, as used herein, represents an oxygen atom.

The formula “N”, as used herein, represents a nitrogen atom.

The formula “S”, as used herein, represents a sulfur atom.

Some compounds of the invention are:

-   3-{5-[2-(3,4-dimethylphenyl)-1-(3-chlorophenyl)ethyl]-1,2,4-oxadiazol-3-yl}-N-methylpyridin-2-amine;-   3-{5-[2-(3,4-dimethylphenyl)-1-(3-bromophenyl)ethyl]-1,2,4-oxadiazol-3-yl}-N-methylpyridin-2-amine;-   3-{5-[2-(3,4-dimethylphenyl)-1-(3-fluorophenyl)ethyl]-1,2,4-oxadiazol-3-yl}-N-methylpyridin-2-amine;-   3-{5-[2-(3,4-dimethylphenyl)-1-(3-methylphenyl)ethyl]-1,2,4-oxadiazol-3-yl}-N-methylpyridin-2-amine;-   3-{5-[2-(3,4-dimethylphenyl)-1-(3-nitrophenyl)ethyl]-1,2,4-oxadiazol-3-yl}-N-methylpyridin-2-amine;-   3-{5-[2-(3,4-dimethylphenyl)-1-(3-methoxyphenyl)ethyl]-1,2,4-oxadiazol-3-yl}-N-methylpyridin-2-amine;-   3-{5-[2-(3,4-dimethylphenyl)-1-(3-ethylphenyl)ethyl]-1,2,4-oxadiazol-3-yl}-N-methylpyridin-2-amine;-   3-{5-[2-(3,4-dimethylphenyl)-1-phenylethyl]-1,2,4-oxadiazol-3-yl}-N-methylpyridin-2-amine;-   3-{5-[2-(3,4-dimethylphenyl)-1-(4-chlorophenyl)ethyl]-1,2,4-oxadiazol-3-yl}-N-methylpyridin-2-amine;-   3-{5-[2-(3,4-dimethylphenyl)-1-(4-methoxyphenyl)ethyl]-1,2,4-oxadiazol-3-yl}-N-methylpyridin-2-amine;-   3-(5-{2-(3,4-dimethylphenyl)-1-[4-(trifluoromethyl)phenyl]ethyl}-1,2,4-oxadiazol-3-yl)-N-methylpyridin-2-amine;-   3-{5-[1-(3-chlorophenyl)-2-phenylethyl]-1,2,4-oxadiazol-3-yl}-N-methylpyridin-2-amine;-   3-{5-[1-(4-chlorophenyl)-2-phenylethyl]-1,2,4-oxadiazol-3-yl}-N-methylpyridin-2-amine;-   3-{5-[1-(4-chlorophenyl)-2-(3,4-dichlorophenyl)ethyl]-1,2,4-oxadiazol-3-yl}-N-methylpyridin-2-amine;-   3-{5-[1-(3-chlorophenyl)-2-(3-methylphenyl)ethyl]-1,2,4-oxadiazol-3-yl}-N-methylpyridin-2-amine;-   3-{5-[1-(3-chlorophenyl)-2-(4-methylphenyl)ethyl]-1,2,4-oxadiazol-3-yl}-N-methylpyridin-2-amine;-   3-{5-[1-(3-chlorophenyl)-2-(4-isobutylphenyl)ethyl]-1,2,4-oxadiazol-3-yl}-N-methylpyridin-2-amine;-   3-{5-[1-(5-chloropyridin-3-yl)-2-(3,4-dimethylphenyl)ethyl]-1,2,4-oxadiazol-3-yl}-N-methylpyridin-2-amine;-   3-{5-[1-(6-chloropyridin-3-yl)-2-(3,4-dimethylphenyl)ethyl]-1,2,4-oxadiazol-3-yl}-N-methylpyridin-2-amine;-   3-{5-[1-(6-chloropyridin-3-yl)-2-(3,5-dimethylphenyl)ethyl]-1,2,4-oxadiazol-3-yl}-N-methylpyridin-2-amine;-   3-{5-[1-(3-chlorophenyl)-2-cyclohexylethyl]-1,2,4-oxadiazol-3-yl}-N-methylpyridin-2-amine;-   3-{5-[1-(3-chlorophenyl)-2-cyclopentylethyl]-1,2,4-oxadiazol-3-yl}-N-methylpyridin-2-amine;-   N-methyl-3-(5-(1-(thiophen-3-yl)-2-(p-tolyl)ethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-amine;-   3-(5-(2-(3,4-dimethylphenyl)-1-(thiophen-3-yl)ethyl)-1,2,4-oxadiazol-3-yl)-N-methylpyridin-2-amine;-   3-(5-(1-(3,5-difluorophenyl)-2-(3,4-dimethylphenyl)ethyl)-1,2,4-oxadiazol-3-yl)-N-methylpyridin-2-amine;-   3-(5-(1,2-diphenylethyl)-1,2,4-oxadiazol-3-yl)-N-methylpyridin-2-amine-   3-(5-(2-(3,4-dimethylphenyl)-1-(3,5-dimethylphenyl)ethyl)-1,2,4-oxadiazol-3-yl)-N-methylpyridin-2-amine;-   N-methyl-3-(5-(1-(thiophen-2-yl)-2-(p-tolyl)ethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-amine;-   3-(5-(2-(3,4-dimethylphenyl)-1-(thiophen-2-yl)ethyl)-1,2,4-oxadiazol-3-yl)-N-methylpyridin-2-amine;-   3-{5-[1-(3,5-difluorophenyl)-2-(3,4-dimethylphenyl)ethyl]-1,2,4-oxadiazol-3-yl}-N-ethylpyridin-2-amine;-   3-{5-[1-(3,5-difluorophenyl)-2-(3,4-dimethylphenyl)ethyl]-1,2,4-oxadiazol-3-yl}-N-propylpyridin-2-amine;-   N-cyclobutyl-3-{5-[1-(3,5-difluorophenyl)-2-(3,4-dimethylphenyl)ethyl]-1,2,4-oxadiazol-3-yl}pyridin-2-amine;-   3-{5-[1-(3,5-difluorophenyl)-2-(3,4-dimethylphenyl)ethyl]-1,2,4-oxadiazol-3-yl}-N,N-dimethylpyridin-2-amine.

Some compounds of Formula I and some of their intermediates have atleast one stereogenic center in their structure. This stereogenic centermay be present in an R or S configuration, said R and S notation is usedin correspondence with the rules described in Pure Appli. Chem. (1976),45, 11-13.

The term “pharmaceutically acceptable salts” refers to salts orcomplexes that retain the desired biological activity of the aboveidentified compounds and exhibit minimal or no undesired toxicologicaleffects. The “pharmaceutically acceptable salts” according to theinvention include therapeutically active, non-toxic base or acid saltforms, which the compounds of Formula I are able to form.

The acid addition salt form of a compound of Formula I that occurs inits free form as a base can be obtained by treating the free base withan appropriate acid such as an inorganic acid, for example, hydrochloricacid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid andthe like; or an organic acid such as for example, acetic, hydroxyacetic,propanoic, lactic, pyruvic, malonic, fumaric acid, maleic acid, oxalicacid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoicacid, tannic acid, pamoic acid, citric, methylsulfonic, ethanesulfonic,benzenesulfonic, formic and the like (Handbook of Pharmaceutical Salts,P. Heinrich Stahal & Camille G. Wermuth (Eds), Verlag Helvetica ChemicaActa-Zürich, 2002, 329-345).

Compounds of Formula I and their salts can be in the form of a solvate,which is included within the scope of the present invention. Suchsolvates include for example hydrates, alcoholates and the like.

With respect to the present invention reference to a compound orcompounds, is intended to encompass that compound in each of itspossible isomeric forms and mixtures thereof unless the particularisomeric form is referred to specifically.

Compounds according to the present invention may exist in differentpolymorphic forms. Although not explicitly indicated in the aboveformula, such forms are intended to be included within the scope of thepresent invention.

The compounds of the invention are indicated for use in treating orpreventing conditions in which there is likely to be a componentinvolving the sphingosine-1-phosphate receptors.

In another embodiment, there are provided pharmaceutical compositionsincluding at least one compound of the invention in a pharmaceuticallyacceptable carrier.

In a further embodiment of the invention, there are provided methods fortreating disorders associated with modulation of sphingosine-1-phosphatereceptors. Such methods can be performed, for example, by administeringto a subject in need thereof a pharmaceutical composition containing atherapeutically effective amount of at least one compound of theinvention.

These compounds are useful for the treatment of mammals, includinghumans, with a range of conditions and diseases that are alleviated byS1P modulation.

-   -   Therapeutic utilities of S1P modulators are:    -   Ocular Diseases: wet and dry age-related macular degeneration,        diabetic retinopathy, retinopathy of prematurity, retinal edema,        geographic atrophy, glaucomatous optic neuropathy,        chorioretinopathy, hypertensive retinopathy, ocular ischemic        syndrome, prevention of inflammation-induced fibrosis in the        back of the eye, various ocular inflammatory diseases including        uveitis, scleritis, keratitis, and retinal vasculitis;    -   Systemic vascular barrier related diseases: various inflammatory        diseases, including acute lung injury, its prevention, sepsis,        tumor metastasis, atherosclerosis, pulmonary edemas, and        ventilation-induced lung injury;    -   Autoimmune diseases and immunosuppression: rheumatoid arthritis,        Crohn's disease, Graves' disease, inflammatory bowel disease,        multiple sclerosis, Myasthenia gravis, Psoriasis, ulcerative        colitis, antoimmune uveitis, renal ischemia/perfusion injury,        contact hypersensitivity, atopic dermititis, and organ        transplantation;    -   Allergies and other inflammatory diseases: urticaria, bronchial        asthma, and other airway inflammations including pulmonary        emphysema and chronic obstructive pulmonary diseases;    -   Cardiac functions: bradycardia, congestional heart failure,        cardiac arrhythmia, prevention and treatment of atherosclerosis,        and ischemia/reperfusion injury;    -   Wound Healing: scar-free healing of wounds from cosmetic skin        surgery, ocular surgery, GI surgery, general surgery, oral        injuries, various mechanical, heat and burn injuries, prevention        and treatment of photoaging and skin ageing, and prevention of        radiation-induced injuries;    -   Bone formation: treatment of osteoporosis and various bone        fractures including hip and ankles;    -   Anti-nociceptive activity: visceral pain, pain associated with        diabetic neuropathy, rheumatoid arthritis, chronic knee and        joint pain, tendonitis, osteoarthritis, neuropathic pains;    -   Anti-fibrosis: ocular, cardiac, hepatic and pulmonary fibrosis,        proliferative vitreoretinopathy, cicatricial pemphigoid,        surgically induced fibrosis in cornea, conjunctiva and tenon;    -   Pains and anti-inflammation: acute pain, flare-up of chronic        pain, musculo-skeletal pains, visceral pain, pain associated        with diabetic neuropathy, rheumatoid arthritis, chronic knee and        joint pain, tendonitis, osteoarthritis, bursitis, neuropathic        pains;    -   CNS neuronal injuries: Alzheimer's disease, age-related neuronal        injuries;    -   Organ transplants: renal, corneal, cardiac and adipose tissue        transplants.

In still another embodiment of the invention, there are provided methodsfor treating disorders associated with modulation ofsphingosine-1-phosphate receptors. Such methods can be performed, forexample, by administering to a subject in need thereof a therapeuticallyeffective amount of at least one compound of the invention, or anycombination thereof, or pharmaceutically acceptable salts, hydrates,solvates, crystal forms and individual isomers, enantiomers, anddiastereomers thereof.

-   -   The present invention concerns the use of a compound of Formula        I or a pharmaceutically acceptable salt thereof, for the        manufacture of a medicament for the treatment of:    -   Ocular Diseases: wet and dry age-related macular degeneration,        diabetic retinopathy, retinopathy of prematurity, retinal edema,        geographic atrophy, glaucomatous optic neuropathy,        chorioretinopathy, hypertensive retinopathy, ocular ischemic        syndrome, prevention of inflammation-induced fibrosis in the        back of the eye, various ocular inflammatory diseases including        uveitis, scleritis, keratitis, and retinal vasculitis;    -   Systemic vascular barrier related diseases: various inflammatory        diseases, including acute lung injury, its prevention, sepsis,        tumor metastasis, atherosclerosis, pulmonary edemas, and        ventilation-induced lung injury;    -   Autoimmune diseases and immunosuppression: rheumatoid arthritis,        Crohn's disease, Graves' disease, inflammatory bowel disease,        multiple sclerosis, Myasthenia gravis, Psoriasis, ulcerative        colitis, antoimmune uveitis, renal ischemia/perfusion injury,        contact hypersensitivity, atopic dermititis, and organ        transplantation;    -   Allergies and other inflammatory diseases: urticaria, bronchial        asthma, and other airway inflammations including pulmonary        emphysema and chronic obstructive pulmonary diseases;    -   Cardiac functions: bradycardia, congestional heart failure,        cardiac arrhythmia, prevention and treatment of atherosclerosis,        and ischemia/reperfusion injury;    -   Wound Healing: scar-free healing of wounds from cosmetic skin        surgery, ocular surgery, GI surgery, general surgery, oral        injuries, various mechanical, heat and burn injuries, prevention        and treatment of photoaging and skin ageing, and prevention of        radiation-induced injuries;    -   Bone formation: treatment of osteoporosis and various bone        fractures including hip and ankles;    -   Anti-nociceptive activity: visceral pain, pain associated with        diabetic neuropathy, rheumatoid arthritis, chronic knee and        joint pain, tendonitis, osteoarthritis, neuropathic pains;    -   Anti-fibrosis: ocular, cardiac, hepatic and pulmonary fibrosis,        proliferative vitreoretinopathy, cicatricial pemphigoid,        surgically induced fibrosis in cornea, conjunctiva and tenon;    -   Pains and anti-inflammation: acute pain, flare-up of chronic        pain, musculo-skeletal pains, visceral pain, pain associated        with diabetic neuropathy, rheumatoid arthritis, chronic knee and        joint pain, tendonitis, osteoarthritis, bursitis, neuropathic        pains;    -   CNS neuronal injuries: Alzheimer's disease, age-related neuronal        injuries;    -   Organ transplants: renal, corneal, cardiac and adipose tissue        transplants.

The actual amount of the compound to be administered in any given casewill be determined by a physician taking into account the relevantcircumstances, such as the severity of the condition, the age and weightof the patient, the patient's general physical condition, the cause ofthe condition, and the route of administration.

The patient will be administered the compound orally in any acceptableform, such as a tablet, liquid, capsule, powder and the like, or otherroutes may be desirable or necessary, particularly if the patientsuffers from nausea. Such other routes may include, without exception,transdermal, parenteral, subcutaneous, intranasal, via an implant stent,intrathecal, intravitreal, topical to the eye, back to the eye,intramuscular, intravenous, and intrarectal modes of delivery.Additionally, the formulations may be designed to delay release of theactive compound over a given period of time, or to carefully control theamount of drug released at a given time during the course of therapy.

In another embodiment of the invention, there are providedpharmaceutical compositions including at least one compound of theinvention in a pharmaceutically acceptable carrier thereof. The phrase“pharmaceutically acceptable” means the carrier, diluent or excipientmust be compatible with the other ingredients of the formulation and notdeleterious to the recipient thereof.

Pharmaceutical compositions of the present invention can be used in theform of a solid, a solution, an emulsion, a dispersion, a patch, amicelle, a liposome, and the like, wherein the resulting compositioncontains one or more compounds of the present invention, as an activeingredient, in admixture with an organic or inorganic carrier orexcipient suitable for enteral or parenteral applications. Inventioncompounds may be combined, for example, with the usual non-toxic,pharmaceutically acceptable carriers for tablets, pellets, capsules,suppositories, solutions, emulsions, suspensions, and any other formsuitable for use. The carriers which can be used include glucose,lactose, gum acacia, gelatin, mannitol, starch paste, magnesiumtrisilicate, talc, corn starch, keratin, colloidal silica, potatostarch, urea, medium chain length triglycerides, dextrans, and othercarriers suitable for use in manufacturing preparations, in solid,semisolid, or liquid form. In addition auxiliary, stabilizing,thickening and coloring agents and perfumes may be used. Inventioncompounds are included in the pharmaceutical composition in an amountsufficient to produce the desired effect upon the process or diseasecondition.

Pharmaceutical compositions containing invention compounds may be in aform suitable for oral use, for example, as tablets, troches, lozenges,aqueous or oily suspensions, dispersible powders or granules, emulsions,hard or soft capsules, or syrups or elixirs. Compositions intended fororal use may be prepared according to any method known in the art forthe manufacture of pharmaceutical compositions and such compositions maycontain one or more agents selected from the group consisting of asweetening agent such as sucrose, lactose, or saccharin, flavoringagents such as peppermint, oil of wintergreen or cherry, coloring agentsand preserving agents in order to provide pharmaceutically elegant andpalatable preparations. Tablets containing invention compounds inadmixture with non-toxic pharmaceutically acceptable excipients may alsobe manufactured by known methods. The excipients used may be, forexample, (1) inert diluents such as calcium carbonate, lactose, calciumphosphate or sodium phosphate; (2) granulating and disintegrating agentssuch as corn starch, potato starch or alginic acid; (3) binding agentssuch as gum tragacanth, corn starch, gelatin or acacia, and (4)lubricating agents such as magnesium stearate, stearic acid or talc. Thetablets may be uncoated or they may be coated by known techniques todelay disintegration and absorption in the gastrointestinal tract andthereby provide a sustained action over a longer period. For example, atime delay material such as glyceryl monostearate or glyceryl distearatemay be employed.

In some cases, formulations for oral use may be in the form of hardgelatin capsules wherein the invention compounds are mixed with an inertsolid diluent, for example, calcium carbonate, calcium phosphate orkaolin. They may also be in the form of soft gelatin capsules whereinthe invention compounds are mixed with water or an oil medium, forexample, peanut oil, liquid paraffin or olive oil.

The pharmaceutical compositions may be in the form of a sterileinjectable suspension. This suspension may be formulated according toknown methods using suitable dispersing or wetting agents and suspendingagents. The sterile injectable preparation may also be a sterileinjectable solution or suspension in a non-toxic parenterally-acceptablediluent or solvent, for example, as a solution in 1,3-butanediol.Sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono- or diglycerides, fatty acids (including oleicacid), naturally occurring vegetable oils like sesame oil, coconut oil,peanut oil, cottonseed oil, etc., or synthetic fatty vehicles like ethyloleate or the like. Buffers, preservatives, antioxidants, and the likecan be incorporated as required.

Invention compounds may also be administered in the form ofsuppositories for rectal administration of the drug. These compositionsmay be prepared by mixing the invention compounds with a suitablenon-irritating excipient, such as cocoa butter, synthetic glycerideesters of polyethylene glycols, which are solid at ordinarytemperatures, but liquefy and/or dissolve in the rectal cavity torelease the drug.

Since individual subjects may present a wide variation in severity ofsymptoms and each drug has its unique therapeutic characteristics, theprecise mode of administration and dosage employed for each subject isleft to the discretion of the practitioner.

The compounds and pharmaceutical compositions described herein areuseful as medicaments in mammals, including humans, for treatment ofdiseases and/or alleviations of conditions which are responsive totreatment by agonists or functional antagonists ofsphingosine-1-phosphate receptors. Thus, in further embodiments of theinvention, there are provided methods for treating a disorder associatedwith modulation of sphingosine-1-phosphate receptors. Such methods canbe performed, for example, by administering to a subject in need thereofa pharmaceutical composition containing a therapeutically effectiveamount of at least one invention compound. As used herein, the term“therapeutically effective amount” means the amount of thepharmaceutical composition that will elicit the biological or medicalresponse of a subject in need thereof that is being sought by theresearcher, veterinarian, medical doctor or other clinician. In someembodiments, the subject in need thereof is a mammal. In someembodiments, the mammal is human.

The present invention concerns also processes for preparing thecompounds of Formula I. The compounds of formula I according to theinvention can be prepared analogously to conventional methods asunderstood by the person skilled in the art of synthetic organicchemistry. The synthetic scheme set forth below, illustrate howcompounds according to the invention can be made.

The following abbreviations are used in the general scheme and in thespecific examples:CDI 1,1′-carbonyl diimidazoleEDCI 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide

NBS N-bromosuccinimide

BPO benzoyl peroxideKOH potassium hydroxideMeOH methanolHCl hydrochloric acidrt room temperatureCDCl₃ deuterated chloroformDMSO-d₆ deuterated dimethyl sulfoxideNaH sodium hydrideTHF tetrahydrofuranNaOEt sodium ethoxyde

Acetonitrile “A” (1 eq) and aldehyde “B” (1 eq) were reacted accordingto the procedure described in Vaccaro. Wayne et al., Journal ofMedicinal Chemistry, 1996, 39(8), 1704-1719 to produce the correspondingpropanoic add intermediate. 1,1′-Carbonyl diimidazole (CDI) (2.10 mmol)in THF was added to 1.90 mmol of acid and the mixture was stirred at rtfor 30 minutes, then N-hydroxy-2-(methylamino)-3-pyridinecarboximidamide (CAS 801303-19-5) (1.9 mmol) was added and the resultingsolution was stirred at rt for 16 hours.

The reaction solution was then transferred to a microwave reactionvessel and heated at 150° C. for 20 min under microwave conditions.After cooling at room temperature (rt), the solvent was removed underreduced pressure. The pyridine derivative was isolated by mediumpressure liquid chromatography (M PLC) using 5 to 10% ethyl acetate inhexane.

DETAILED DESCRIPTION OF THE INVENTION

It is to be understood that both the foregoing general description andthe following detailed description are exemplary and explanatory onlyand are not restrictive of the invention claimed. As used herein, theuse of the singular includes the plural unless specifically statedotherwise.

It will be readily apparent to those skilled in the art that some of thecompounds of the invention may contain one or more asymmetric centers,such that the compounds may exist in enantiomeric as well as indiastereomeric forms. Unless it is specifically noted otherwise, thescope of the present invention includes all enantiomers, diastereomersand racemic mixtures. Some of the compounds of the invention may formsalts with pharmaceutically acceptable acids or bases, and suchpharmaceutically acceptable salts of the compounds described herein arealso within the scope of the invention.

The present invention includes all pharmaceutically acceptableisotopically enriched compounds. Any compound of the invention maycontain one or more isotopic atoms enriched or different than thenatural ratio such as deuterium ²H (or D) in place of hydrogen ¹H (or H)or use of ¹³C enriched material in place of ¹²C and the like. Similarsubstitutions can be employed for N, O and S. The use of isotopes mayassist in analytical as well as therapeutic aspects of the invention.For example, use of deuterium may increase the in vivo half-life byaltering the metabolism (rate) of the compounds of the invention. Thesecompounds can be prepared in accord with the preparations described byuse of isotopically enriched reagents.

The following examples are for illustrative purposes only and are notintended, nor should they be construed as limiting the invention in anymanner. Those skilled in the art will appreciate that variations andmodifications of the following examples can be made without exceedingthe spirit or scope of the invention.

As will be evident to those skilled in the art, individual isomericforms can be obtained by separation of mixtures thereof in conventionalmanner. For example, in the case of diasteroisomeric isomers,chromatographic separation may be employed.

Compound names were generated with ACD version 8.

In general, characterization of the compounds is performed according tothe following methods: Proton nuclear magnetic resonance (¹H NMR)spectra were recorded on a Varian 300 or 600 MHz spectrometer indeuterated solvent. Chemical shifts were reported as δ (delta) values inparts per million (ppm) relative to tetramethylsilane (TMS) as aninternal standard (0.00 ppm) and multiplicities were reported as s,singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad.Data were reported in the following format: chemical shift(multiplicity, coupling constant(s) J in hertz (Hz), integratedintensity).

All the reagents, solvents, catalysts for which the synthesis is notdescribed are purchased from chemical vendors such as Sigma Aldrich,Fluka, Bio-Blocks, Combi-blocks, TCI, VWR, Lancaster, Oakwood, TransWorld Chemical, Alfa, Fisher, Maybridge, Frontier, Matrix, Ukrorgsynth,Toronto, Ryan Scientific, SiliCycle, Anaspec, Syn Chem, Chem-Impex,MIC-scientific, Ltd; however some known intermediates, were preparedaccording to published procedures.

Usually the compounds of the invention were purified by columnchromatography (Auto-column) on an Teledyne-ISCO CombiFlash with asilica column, unless noted otherwise.

The following synthetic schemes illustrate how compounds according tothe invention can be made. Those skilled in the art will be routinelyable to modify and/or adapt the following schemes to synthesize anycompound of the invention covered by Formula I.

Example 1 Compound 1N-methyl-3-(5-(1-(thiophen-3-yl)-2-(p-tolyl)ethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-amine

2-(Thiophen-3-yl)-3-(p-tolyl)propanoic acid was obtained fromcommercially available 2-(thiophen-3-yl)acetonitrile (10.00 g, 81.18mmol), 4-tolylaldehyde (10.00 g, 83.23 mmol) sodium ethoxide (20 w/v %in ethanol, 50.00 mL), sodium borohydride (5.00 g, 131.58 mmol) andpotassium hydride (5.00 g, 89.11 mmol) according to the protocols asoutlined in Vaccaro, Wayne et al. Journal of Medicinal Chemistry, 1996,39(8), 1704-1719. This acid was used in the next synthetic step withoutfurther purification.Crude 2-(thiophen-3-yl)-3-(p-tolyl)propanoic acid (, 2.40 g, 9.74 mmol),carbonyl diimidazole (1.90 g, 11.73 mmol) andN-hydroxy-2-(methylamino)-3-pyridinecarboximidamide (1.66 g, 10.00 mmol)reacted according to the general procedure described above.

¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.19 (s, 3H), 2.99 (d, J=4.69 Hz, 3H),3.33-3.38 (m, 1H), 3.43-3.51 (m, 1H), 4.98 (t, J=8.06 Hz, 1H), 6.71 (dd,J=7.47, 4.83 Hz, 1H), 6.91-7.04 (m, 3H), 7.05-7.14 (m, 2H), 7.15-7.28(m, 1H), 7.40-7.62 (m, 2H), 8.18 (dd, J=7.62, 1.76 Hz, 1H), 8.26 (dd,J=4.83, 1.90 Hz, 1H).

Compounds 2 through 34 were prepared from the carboxylic acidintermediate obtained from the corresponding acetonitrile derivative,the corresponding aldehyde derivative and the correspondingpyridinecarboximidamide in a similar manner to the procedure describedin Example 1 in the general procedure described above. The carboxylicacid intermediate and the results are tabulated below in Table 1.

TABLE 1 Comp Carboxylic acid ¹H NMR δ (ppm) for No. IUPAC nameintermediate Compound 2

2-(3-chlorophenyl)- 3-(3,4- dimethylphenyl) propanoic acid ¹H NMR (300MHz, CD₃OD) δ ppm 2.15 (s, 6 H) 3.02-3.07 (m, 3 H) 3.24-3.32 (m, 1 H)3.52 (dd, J = 13.63, 8.35 Hz, 1 H) 4.69 (t, J = 8.06 Hz, 1 H) 6.71 (dd,J = 7.62, 4.98 Hz, 1 H) 6.80-6.85 (m, 1 H) 6.90-6.96 (m, 2 H) 7.26-7.33(m, 3 H) 7.40- 7.42 (m, 1 H) 8.19 (dd, J = 4.98, 2.05 Hz, 1 H) 8.34 (dd,J = 7.62, 1.76 Hz, 1 H) 3

2-(3-bromophenyl)- 3-(3,4- dimethylphenyl) propanoic acid ¹H NMR (300MHz, CD₃OD) δ ppm 2.15 (s, 6 H) 3.03-3.08 (m, 3 H) 3.23-3.31 (m, 1 H)3.52 (dd, J = 13.63, 8.35 Hz, 1 H) 4.68 (t, J = 8.06 Hz, 1 H) 6.71 (dd,J = 7.62, 4.98 Hz, 1 H) 6.80-6.86 (m, 1 H) 6.89-6.96 (m, 2 H) 7.20-7.27(m, 1 H) 7.36 (d, J = 7.62 Hz, 1 H) 7.43 (d, J = 7.62 Hz, 1 H) 7.56 (s,1 H) 8.19 (dd, J = 4.98, 1.76 Hz, 1 H) 8.34 (dd, J = 7.62, 1.76 Hz, 1 H)4

2-(3-fluorophenyl)-3- (3,4- dimethylphenyl) propanoic acid ¹H NMR (300MHz, CD₃OD) δ ppm 2.14 (s, 6 H) 3.04-3.07 (m, 3 H) 3.24-3.32 (m, 1 H)3.52 (dd, J = 13.77, 8.50 Hz, 1 H) 4.70 (t, J = 7.91 Hz, 1 H) 6.71 (dd,J = 7.62, 4.98 Hz, 1 H) 6.81-6.86 (m, 1 H) 6.90-6.98 (m, 2 H) 6.99-7.04(m, 1 H) 7.11- 7.22 (m, 2 H) 7.28- 7.39 (m, 1 H) 8.19 (dd, J = 4.98,2.05 Hz, 1 H) 8.34 (dd, J = 7.62, 1.76 Hz, 1 H) 5

2-(3-methylphenyl)- 3-(3,4- dimethylphenyl) propanoic acid ¹H NMR (300MHz, CD₃OD) δ ppm 2.15 (s, 6 H) 2.31 (s, 3 H) 3.04- 3.08 (m, 3 H)3.24-3.32 (m, 1 H) 3.53 (dd, J = 13.48, 8.79 Hz, 1 H) 4.61 (dd, J =8.79, 7.33 Hz, 1 H) 6.72 (dd, J = 7.62, 4.98 Hz, 1 H) 6.81-6.88 (m, 1 H)6.89- 6.96 (m, 2 H) 7.05- 7.11 (m, 1 H) 7.14-7.24 (m, 3 H) 8.19 (dd, J =4.98, 1.76 Hz, 1 H) 8.34 (dd, J = 7.62, 2.05 Hz, 1 H) 6

2-(3-nitrophenyl)-3- (3,4- dimethylphenyl) propanoic acid ¹H NMR (300MHz, CD₃OD) δ ppm 2.14 (s, 6 H) 3.03-3.08 (m, 3 H) 3.32-3.39 (m, 1 H)3.58 (dd, J = 13.63, 8.06 Hz, 1 H) 4.89 (t, J = 8.01 Hz, 1 H) 6.71 (dd,J = 7.62, 4.98 Hz, 1 H) 6.80-6.86 (m, 1 H) 6.90-6.95 (m, 2 H) 7.52-7.60(m, 1 H) 7.79 (d, J = 7.91 Hz, 1 H) 8.11- 8.17 (m, 1 H) 8.19 (dd, J =4.98, 1.76 Hz, 1 H) 8.28 (s, 1 H) 8.34 (dd, J = 7.33, 1.76 Hz, 1 H) 7

2-(3- methoxyphenyl)-3- (3,4- dimethylphenyl) propanoic acid ¹H NMR (300MHz, CD₃OD) δ ppm 2.13 (s, 6 H) 3.02-3.06 (m, 3 H) 3.23-3.30 (m, 1 H)3.50 (dd, J = 13.63, 8.64 Hz, 1 H) 3.74 (s, 3 H) 4.61 (dd, J = 8.50,7.62 Hz, 1 H) 6.68 (dd, J = 7.62, 4.98 Hz, 1 H) 6.79-6.85 (m, 2 H)6.89-6.96 (m, 4 H) 7.19-7.26 (m, 1 H) 8.17 (dd, J = 4.98, 1.76 Hz, 1 H)8.32 (dd, J = 7.47, 1.90 Hz, 1 H) 8

2-(3-ethylphenyl)-3- (3,4- dimethylphenyl) propanoic acid ¹H NMR (300MHz, CD₃OD) δ ppm 1.17 (t, J = 7.62 Hz, 3 H) 2.13 (s, 6 H) 2.59 (q, J =7.62 Hz, 2 H) 3.01-3.08 (m, 3 H) 3.22-3.31 (m, 1 H) 3.52 (dd, J = 13.63,8.64 Hz, 1 H) 4.61 (t, J = 7.91 Hz, 1 H) 6.70 (dd, J = 7.62, 4.98 Hz, 1H) 6.79-6.85 (m, 1 H) 6.86-6.95 (m, 2 H) 7.10 (d, J = 6.74 Hz, 1 H)7.13-7.27 (m, 3 H) 8.15- 8.20 (m, 1 H) 8.33 (dd, J = 7.62, 1.76 Hz, 1H). 9

3-(3,4- dimethylphenyl)-2- phenylpropanoic acid ¹H NMR (300 MHz, CD₃OD)δ ppm 2.14 (s, 6 H) 3.05 (s, 3 H) 3.24-3.31 (m, 1 H) 3.53 (dd, J =13.63, 8.64 Hz, 1 H) 4.65 (dd, J = 8.50, 7.33 Hz, 1 H) 6.70 (dd, J =7.62, 4.98 Hz, 1 H) 6.80-6.85 (m, 1 H) 6.89- 6.94 (m, 2 H) 7.24- 7.40(m, 5 H) 8.18 (dd, J = 4.98, 2.05 Hz, 1 H) 8.33 (dd, J = 7.62, 1.76 Hz,1 H). 10

2-(4-chlorophenyl)- 3-(3,4- dimethylphenyl) propanoic acid ¹H NMR (300MHz, CD₃OD) δ ppm 2.14 (s, 6 H) 3.03-3.07 (m, 3 H) 3.22-3.31 (m, 1 H)3.52 (dd, J = 13.77, 8.20 Hz, 1 H) 4.67 (t, J = 8.06 Hz, 1 H) 6.71 (dd,J = 7.62, 4.98 Hz, 1 H) 6.79-6.84 (m, 1 H) 6.89- 6.95 (m, 2 H) 7.28-7.38 (m, 4 H) 8.19 (dd, J = 4.98, 1.76 Hz, 1 H) 8.34 (dd, J = 7.62, 2.05Hz, 1 H) 11

2-(4- methoxyphenyl)-3- (3,4- dimethylphenyl) propanoic acid ¹H NMR (300MHz, CD₃OD) δ ppm 2.14 (s, 6 H) 3.04-3.09 (m, 3 H) 3.20-3.29 (m, 1 H)3.50 (dd, J = 13.48, 8.50 Hz, 1 H) 3.75 (s, 3 H) 4.59 (t, J = 8.06 Hz, 1H) 6.71 (dd, J = 7.62, 4.98 Hz, 1 H) 6.78-6.96 (m, 5 H) 7.24- 7.33 (m, 2H) 8.18 (dd, J = 4.98, 1.76 Hz, 1 H) 8.34 (dd, J = 7.62, 2.05 Hz, 1 H)12

2-(4- trifluoromethylphenyl)- 3-(3,4- dimethylphenyl) propanoic acid ¹HNMR (300 MHz, CD₃OD) δ ppm 2.14 (s, 3 H) 2.15 (s, 3 H) 3.05- 3.08 (m, 3H) 3.28-3.31 (m, 1H) 3.57 (dd, J = 13.77, 8.20 Hz, 1 H) 4.80 (t, J =7.91 Hz, 1 H) 6.72 (dd, J = 7.62, 4.98 Hz, 1 H) 6.80-6.86 (m, 1 H)6.89-6.96 (m, 2 H) 7.60 (m, 4 H) 8.19 (dd, J = 4.98, 1.76 Hz, 1 H) 8.35(dd, J = 7.62, 1.76 Hz, 1 H) 13

2-(3-chlorophenyl)- 3-phenylpropanoic acid ¹H NMR (300 MHz, CD₃OD) δ ppm3.04- 3.07 (m, 3 H) 3.37 (dd, J = 13.77, 7.91 Hz, 1 H) 3.61 (dd, J =13.77, 8.20 Hz, 1 H) 4.73 (t, J = 7.91 Hz, 1 H) 6.71 (dd, J = 7.62, 4.98Hz, 1 H) 7.12-7.22 (m, 5 H) 7.26- 7.33 (m, 3 H) 7.41 (m, 1 H) 8.19 (dd,J = 4.98, 1.76 Hz, 1 H) 8.34 (dd, J = 7.62, 2.05 Hz, 1 H) 14

2-(4-chlorophenyl)- 3-phenylpropanoic acid ¹H NMR (300 MHz, CD₃OD) δ ppm3.05- 3.09 (m, 3 H) 3.37 (dd, J = 13.77, 7.91 Hz, 1 H) 3.61 (dd, J =13.77, 8.20 Hz, 1 H) 4.73 (t, J = 7.91 Hz, 1 H) 6.74 (dd, J = 7.62, 4.98Hz, 1 H) 7.12-7.22 (m, 5 H) 7.31- 7.38 (m, 4 H) 8.18-8.22 (m, 1 H) 8.34(dd, J = 7.62, 2.05 Hz, 1 H) 15

2-(4-chlorophenyl)- 3-(3,4- dichlorophenyl) propanoic acid ¹H NMR (300MHz, CD₃OD) δ ppm 3.06- 3.09 (m, 3 H) 3.38 (dd, J = 13.77, 8.20 Hz, 1 H)3.62 (dd, J = 13.77, 7.62 Hz, 1 H) 4.75 (t, J = 8.06 Hz, 1 H) 6.74 (dd,J = 7.62, 4.98 Hz, 1 H) 7.07 (dd, J = 8.20, 2.05 Hz, 1 H) 7.32-7.39 (m,6 H) 8.21 (dd, J = 4.98, 2.05 Hz, 1 H) 8.37 (dd, J = 7.62, 1.76 Hz, 1 H)16

2-(3-chlorophenyl)- 3-(3- methylphenyl) propanoic acid ¹H NMR (300 MHz,CD₃OD) δ ppm 2.23 (s, 3 H) 3.08 (s, 3 H) 3.31-3.39 (m, 1 H) 3.58 (dd, J= 13.77, 8.20 Hz, 1 H) 4.73 (t, J = 7.91 Hz, 1 H) 6.75 (dd, J = 7.62,4.98 Hz, 1 H) 6.90-7.00 (m, 3 H) 7.04-7.11 (m, 1 H) 7.27-7.34 (m, 3 H)7.42 (s, 1 H) 8.20 (dd, J = 4.98, 2.05 Hz, 1 H) 8.38 (dd, J = 7.62, 1.76Hz, 1 H) 17

2-(3-chlorophenyl)- 3-(4- isobutylphenyl) propanoic acid ¹H NMR (300MHz, CD₃OD) δ ppm 0.83 (d, J = 6.74 Hz, 6 H) 1.77 (dt, J = 13.48, 6.74Hz, 1 H) 2.38 (d, J = 7.33 Hz, 2 H) 3.06 (s, 3 H) 3.32-3.39 (m, 1 H)3.58 (dd, J = 13.48, 8.20 Hz, 1 H) 4.70 (t, J = 8.06 Hz, 1 H) 6.72 (dd,J = 7.62, 4.98 Hz, 1 H) 6.93-7.07 (m, 4 H) 7.25-7.35 (m, 3 H) 7.38 (s, 1H) 8.19 (dd, J = 4.98, 1.76 Hz, 1 H) 8.35 (dd, J = 7.47, 1.90 Hz, 1 H)18

2-(5-chloropyridin-3- yl)-3-(3,4- dimethylphenyl) propanoic acid ¹H NMR(300 MHz, CD₃OD) δ ppm 2.15 (s, 6 H) 3.04-3.09 (m, 3 H) 3.28-3.36 (m,1H) 3.57 (dd, J = 13.63, 7.76 Hz, 1 H) 4.86 (t, J = 7.91 Hz, 1 H) 6.71(dd, J = 7.62, 4.98 Hz, 1 H) 6.78-6.84 (m, 1 H) 6.88-6.98 (m, 2 H) 7.96(t, J = 2.05 Hz, 1 H) 8.20 (dd, J = 4.98, 1.76 Hz, 1 H) 8.33 (dd, J =7.62, 1.76 Hz, 1 H) 8.45 (dd, J = 7.33, 2.05 Hz, 2 H) 19

2-(6-chloropyridin-3- yl)-3-(3,4- dimethylphenyl) propanoic acid ¹H NMR(300 MHz, CD₃OD) δ ppm 2.16 (s, 6 H) 3.04-3.08 (m, 3 H) 3.25-3.33 (m, 1H) 3.57 (dd, J = 13.63, 7.47 Hz, 1 H) 4.82 (t, J = 7.91 Hz, 1 H) 6.73(dd, J = 7.62, 4.98 Hz, 1 H) 6.82 (d, J = 7.91 Hz, 1 H) 6.89-6.98 (m, 2H) 7.43 (d, J = 8.50 Hz, 1 H) 7.91 (dd, J = 8.50, 2.64 Hz, 1 H) 8.21(dd, J = 4.98, 2.05 Hz, 1 H) 8.30 (d, J = 2.34 Hz, 1 H) 8.35 (dd, J =7.77, 1.90 Hz, 1 H) 20

2-(6-chloropyridin-3- yl)-3-(3,5- dimethylphenyl) propanoic acid ¹H NMR(300 MHz, CD₃OD) δ ppm 2.20 (s, 3 H) 2.23 (s, 3 H) 3.03-3.07 (m, 3 H)3.28-3.35 (m, 1 H) 3.62 (dd, J = 13.77, 7.62 Hz, 1 H) 4.78 (t, J = 7.91Hz, 1 H) 6.71 (dd, J = 7.62, 4.98 Hz, 1 H) 6.81 (s, 2 H) 6.93 (s, 1 H)7.42 (d, J = 8.20 Hz, 1 H) 7.89 (dd, J = 8.20, 2.64 Hz, 1 H) 8.19 (dd, J= 4.98, 1.76 Hz, 1 H) 8.28 (d, J = 2.34 Hz, 1 H) 8.34 (dd, J = 7.47,1.90 Hz, 1 H) 21

2-(3-chlorophenyl)- 3- cyclohexylpropanoic acid ¹H NMR (300 MHz, CD₃OD)δ ppm 0.92- 1.30 (m, 6 H) 1.56-1.84 (m, 5 H) 1.92-2.04 (m, 1 H)2.10-2.25 (m, 1 H) 3.01-3.11 (m, 3 H) 4.53 (t, J = 7.91 Hz, 1 H) 6.70(dd, J = 7.62, 4.98 Hz, 1 H) 7.25-7.37 (m, 3 H) 7.45 (s, 1 H) 8.18 (dd,J = 4.98, 1.76 Hz, 1 H) 8.33 (dd, J = 7.62, 1.76 Hz, 1 H) 22

2-(3-chlorophenyl)- 3- cyclopentylpropanoic acid ¹H NMR (300 MHz, CD₃OD)δ ppm 1.05-1.15 (m, 2 H) 1.43-1.84 (m, 7 H) 2.08-2.20 (m, 1 H) 2.23-2.35(m, 1 H) 3.02- 3.10 (m, 3 H) 4.43 (t, J = 7.91 Hz, 1 H) 6.71 (dd, J =7.62, 4.98 Hz, 1 H) 7.26-7.39 (m, 3 H) 7.46 (d, J = 0.88 Hz, 1 H) 8.19(dd, J = 4.98, 1.76 Hz, 1 H) 8.34 (dd, J = 7.62, 1.76 Hz, 1 H). 23

2-(3,5- difluorophenyl)-3- (3,4- dimethylphenyl) propanoic acid : ¹H NMR(300 MHz, CDCl₃) δ ppm 2.18 (s, 6 H), 3.13 (d, J = 4.69 Hz, 3 H), 3.28(d, J = 7.33 Hz, 1 H), 3.51 (d, J = 8.50 Hz, 1 H), 4.37-4.68 (m, 1 H),6.54-6.84 (m, 3 H), 6.86- 7.10 (m, 5 H), 8.22- 8.42 (m, 2 H). 24

2,3- diphenylpropanoic acid ¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.98 (d, J =4.69 Hz, 3 H), 3.37 (dd, J = 13.63, 7.76 Hz, 1 H), 3.59 (dd, J = 13.77,8.50 Hz, 1 H), 4.91 (t, J = 8.06 Hz, 1 H), 6.72 (dd, J = 7.62, 4.98 Hz,1 H), 6.97 (d, J = 4.69 Hz, 1 H), 7.06-7.18 (m, 1 H), 7.18-7.22 (m, 3H), 7.23- 7.37 (m, 3 H), 7.39- 7.47 (m, 2 H), 8.20 (dd, J = 7.62, 2.05Hz, 1 H), 8.26 (dd, J = 4.69, 2.05 Hz, 1 H). 25

2-(3,5- difluorophenyl)-3- (3,4- dimethylphenyl) propanoic acid ¹H NMR(300 MHz, DMSO-d₆) δ ppm 2.08 (s, 3 H), 2.10 (s, 3 H), 2.22 (s, 6 H),2.98 (d, J = 4.69 Hz, 3 H), 3.24 (dd, J = 13.92, 6.59 Hz, 1 H), 3.47(dd, J = 13.77, 9.38 Hz, 1 H), 4.65-4.83 (m, 1 H), 6.70 (dd, J = 7.62,4.69 Hz, 1 H), 6.86-6.94 (m, 3 H), 6.94-7.00 (m, 1 H), 7.04 (s, 3 H),8.19 (dd, J = 7.62, 1.76 Hz, 1 H), 8.25 (dd, J = 4.83, 1.90 Hz, 1 H). 26

2-(thiophen-2-yl)-3- (p-tolyl)propanoic acid ¹H NMR (300 MHz, CDCl₃) δppm 2.27 (s, 2 H), 3.13 (d, J = 4.69 Hz, 2 H), 3.31-3.47 (m, 1 H),3.49-3.81 (m, 1 H), 4.87 (t, J = 7.91 Hz, 1 H), 6.66 (dd, J = 7.47, 5.13Hz, 1 H), 6.83-7.12 (m, 5 H), 7.24 (dd, J = 5.13, 1.03 Hz, 1 H),8.14-8.41 (m, 2H). 27

3-(3,4- dimethylphenyl)-2- (thiophen-2- yl)propanoic acid ¹H NMR (300MHz, CDCl₃) δ ppm 2.18 (s, 6 H), 3.13 (d, J = 4.69 Hz, 3 H), 3.40 (d, J= 6.74 Hz, 1 H), 3.54 (d, J = 8.50 Hz, 1 H), 4.87 (s, 1 H), 6.66 (dd, J= 7.33, 5.27 Hz, 1 H), 6.84 (d, J = 7.62 Hz, 1 H), 6.90-7.13 (m, 5 H),7.23 (d, J = 4.69 Hz, 1 H), 8.23-8.38 (m, 2 H). 28

(3-chlorophenyl)-3- (4- methylphenyl) propanoic acid ¹H NMR (300 MHz,CD₃OD) δ ppm 2.22 (s, 3 H) 3.01-3.08 (m, 3 H) 3.27-3.34 (m, 1 H) 3.55(dd, J = 13.77, 8.20 Hz, 1 H) 4.68 (t, J = 8.06 Hz, 1 H) 6.69 (dd, J =7.62, 4.98 Hz, 1 H) 6.96-7.04 (m, 4 H) 7.24-7.33 (m, 3 H) 7.40 (s, 1 H)8.17 (dd, J = 4.98, 1.76 Hz, 1 H) 8.32 (dd, J = 7.62, 1.76 Hz, 1 H) 29

3-(3,4- dimethylphenyl)-2- (thiophen-3- yl)propanoic acid ¹H NMR (300MHz, CDCl₃) δ ppm 2.17 (s, 7 H), 3.12 (d, J = 4.69 Hz, 3 H), 3.22-3.39(m, 1 H), 3.42-3.60 (m, 1 H), 4.70 (t, J = 7.77 Hz, 1 H), 6.65 (dd, J =7.33, 5.27 Hz, 1 H), 6.80 (d, J = 7.33 Hz, 1 H), 6.87 (s, 1 H), 6.96 (d,J = 7.91 Hz, 1 H), 7.02 (d, J = 3.52 Hz, 1 H), 7.09- 7.14 (m, 1 H), 7.17(s, 1 H), 7.29 (dd, J = 4.83, 3.08 Hz, 1 H), 8.20-8.39 (m, 2 H). 30

2-(3-nitrophenyl)-3- (3,4- dimethylphenyl) propanoic acid ¹H NMR (300MHz, DMSO-d₆) δ ppm 2.09 (s, 5 H), 2.98 (d, J = 4.69 Hz, 3 H), 3.28-3.36(m, 1 H), 3.45-3.64 (m, 1 H), 5.08 (s, 1 H), 6.72 (dd, J = 7.62, 4.69Hz, 1 H), 6.82-7.07 (m, 4 H), 7.46-7.69 (m, 2 H), 7.72-7.87 (m, 2 H),8.10-8.34 (m, 2 H). 31

2-(3,5- difluorophenyl)-3- (3,4- dimethylphenyl) propanoic acid2-(ethylamino)-N′- hydroxynicotinimidamide ¹H NMR (300 MHz, DMSO-d₆) δppm 1.04- 1.21 (m, 3 H), 2.09 (s, 3 H), 2.10 (s, 3 H), 3.23- 3.37 (m, 1H), 3.42-3.58 (m, 3 H), 4.00 (q, J = 7.13 Hz, 1 H), 4.99 (t, J = 8.06Hz, 1 H), 6.71 (dd, J = 7.62, 4.98 Hz, 1 H), 6.83-7.04 (m, 4 H), 7.09-7.29 (m, 3H), 8.14- 8.28 (m, 2 H) 32

2-(3,5- difluorophenyl)-3- (3,4- dimethylphenyl) propanoic acid2-(propylamino)-N′- hydroxynicotinimidamide ¹H NMR (300 MHz, DMSO-d₆) δppm 0.85- 0.96 (m, 3 H), 1.49-1.65 (m, 2 H), 2.09 (s, 3 H), 2.10 (s, 3H), 3.24-3.36 (m, 1 H), 3.40-3.56 (m, 3 H), 4.98 (t, J = 8.06 Hz, 1 H),6.71 (dd, J = 7.62, 4.69 Hz, 1 H), 6.86-7.07 (m, 5 H), 7.11-7.28 (m, 3H), 8.15-8.27 (m, 2 H) 33

2-(3,5- difluorophenyl)-3- (3,4- dimethylphenyl) propanoic acid2-(cyclobutylamino)- N′- hydroxynicotinimidamide ¹H NMR (300 MHz,DMSO-d₆) δ ppm 1.57- 1.76 (m, 2 H), 1.85 (d, J = 2.93 Hz, 2 H), 2.09 (s,3 H), 2.10 (s, 3 H), 2.24- 2.41 (m, 2 H), 3.26-34 (m, 1 H), 3.42-3.58(m, 1 H), 4.40-4.67 (m, 1 H), 4.99 (s, 1 H), 6.72 (dd, J = 7.62, 4.98Hz, 1 H), 6.85-6.97 (m, 2 H), 7.00 (s, 1 H), 7.09-7.16 (m, 2 H), 7.23(dd, J = 8.50, 2.34 Hz, 2 H), 8.12-8.25 (m, 2 H). 34

2-(3,5- difluorophenyl)-3- (3,4- dimethylphenyl) propanoic acid2-(dimethylamino)- N′- hydroxynicotinimidamide (CAS 1016701-63-5) ¹H NMR(300 MHz, DMSO-d₆) δ ppm 2.10 (s, 6 H), 2.65 (s, 6 H), 3.25- 3.32 (m, 1H), 3.38-3.54 (m, 1 H), 4.89-5.06 (m, 1 H), 6.79 (dd, J = 7.62, 4.69 Hz,1 H), 6.96 (d, J = 14.94 Hz, 3 H), 7.08- 7.31 (m, 3 H), 7.76 (dd, J =7.47, 1.90 Hz, 1 H), 8.24 (dd, J = 4.69, 2.05 Hz, 1 H)

Biological Data

Compounds were synthesized and tested for S1P1 activity using the GTPγ³⁵S binding assay. These compounds may be assessed for their ability toactivate or block activation of the human S1P1 receptor in cells stablyexpressing the S1P1 receptor.

GTP γ³⁵S binding was measured in the medium containing (mM) HEPES 25, pH7.4, MgCl₂ 10, NaCl 100, dithitothreitol 0.5, digitonin 0.003%, 0.2 nMGTP γ³⁵S, and 5 μg membrane protein in a volume of 150 μl. Testcompounds were included in the concentration range from 0.08 to 5,000 nMunless indicated otherwise. Membranes were incubated with 100 μM5′-adenylylimmidodiphosphate for 30 min, and subsequently with 10 μM GDPfor 10 min on ice. Drug solutions and membrane were mixed, and thenreactions were initiated by adding GTP γ³⁵S and continued for 30 min at25° C. Reaction mixtures were filtered over Whatman GF/B filters undervacuum, and washed three times with 3 mL of ice-cold buffer (HEPES 25,pH7.4, MgCl₂ 10 and NaCl 100). Filters were dried and mixed withscintillant, and counted for ³⁵S activity using a β-counter.Agonist-induced GTP γ³⁵S binding was obtained by subtracting that in theabsence of agonist. Binding data were analyzed using a non-linearregression method. In case of antagonist assay, the reaction mixturecontained 10 nM S1P in the presence of test antagonist at concentrationsranging from 0.08 to 5000 nM.

Table 2 shows activity potency: S1P1 receptor from GTP γ³⁵S: nM, (EC₅₀).Activity potency: S1P1 receptor from GTP γ³⁵S: nM, (EC₅₀),

TABLE 2 S1P1 IUPAC name EC₅₀ (nM)3-{5-[2-(3,4-dimethylphenyl)-1-(4-methoxyphenyl)ethyl]- 13301,2,4-oxadiazol-3-yl}-N-methylpyridin-2-amine3-{5-[1-(3-chlorophenyl)-2-(4-isobutylphenyl)ethyl]-1,2,4- 2090oxadiazol-3-yl}-N-methylpyridin-2-amine3-{5-[2-(3,4-dimethylphenyl)-1-(3-methylphenyl)ethyl]-1,2,4- 50.2oxadiazol-3-yl}-N-methylpyridin-2-amine3-(5-{2-(3,4-dimethylphenyl)-1-[3- 167(trifluoromethyl)phenyl]ethyl}-1,2,4-oxadiazol-3-yl)-N-methylpyridin-2-amine3-{5-[1-(4-chlorophenyl)-2-(3,4-dichlorophenyl)ethyl]- 20201,2,4-oxadiazol-3-yl}-N-methylpyridin-2-amine3-{5-[2-(3,4-dimethylphenyl)-1-(3-nitrophenyl)ethyl]-1,2,4- 86.4oxadiazol-3-yl}-N-methylpyridin-2-amine3-{5-[2-(3,4-dimethylphenyl)-1-phenylethyl]-1,2,4- 912oxadiazol-3-yl}-N-methylpyridin-2-amine3-{5-[2-(3,4-dimethylphenyl)-1-(3,5-dimethylphenyl)ethyl]- 1611,2,4-oxadiazol-3-yl}-N-methylpyridin-2-amine3-{5-[2-(3,4-dimethylphenyl)-1-(3-thienyl)ethyl]-1,2,4- 296oxadiazol-3-yl}-N-methylpyridin-2-amine3-[5-(1,2-diphenylethyl)-1,2,4-oxadiazol-3-yl]-N- 1240methylpyridin-2-amine3-{5-[1-(6-chloropyridin-3-yl)-2-(3,5-dimethylphenyl)ethyl]- 27601,2,4-oxadiazol-3-yl}-N-methylpyridin-2-amine3-{5-[2-(3,4-dimethylphenyl)-1-(3-ethylphenyl)ethyl]-1,2,4- 61.8oxadiazol-3-yl}-N-methylpyridin-2-amine3-{5-[2-(3,4-dimethylphenyl)-1-(2-thienyl)ethyl]-1,2,4- 524oxadiazol-3-yl}-N-methylpyridin-2-amine3-{5-[1-(3-chlorophenyl)-2-cyclohexylethyl]-1,2,4- 348oxadiazol-3-yl}-N-methylpyridin-2-amine3-{5-[1-(3-chlorophenyl)-2-(3-methylphenyl)ethyl]-1,2,4- 125oxadiazol-3-yl}-N-methylpyridin-2-amineN-methyl-3-{5-[2-(4-methylphenyl)-1-(3-thienyl)ethyl]- 5331,2,4-oxadiazol-3-yl}pyridin-2-amine3-{5-[1-(6-chloropyridin-3-yl)-2-(3,4-dimethylphenyl)ethyl]- 2741,2,4-oxadiazol-3-yl}-N-methylpyridin-2-amine3-{5-[1-(3-chlorophenyl)-2-phenylethyl]-1,2,4- 112oxadiazol-3-yl}-N-methylpyridin-2-amine3-{5-[1-(4-chlorophenyl)-2-(3,4-dimethylphenyl)ethyl]- 4701,2,4-oxadiazol-3-yl}-N-methylpyridin-2-amine3-{5-[1-(3-chlorophenyl)-2-cyclopentylethyl]-1,2,4- 1860oxadiazol-3-yl}-N-methylpyridin-2-amine3-(5-{2-(3,4-dimethylphenyl)-1-[4- 2260(trifluoromethyl)phenyl]ethyl}-1,2,4-oxadiazol-3-yl)-N-methylpyridin-2-amine3-{5-[1-(3-bromophenyl)-2-(3,4-dimethylphenyl)ethyl]- 50.61,2,4-oxadiazol-3-yl}-N-methylpyridin-2-amine3-{5-[1-(3-chlorophenyl)-2-(3,4-dimethylphenyl)ethyl]- 66.41,2,4-oxadiazol-3-yl}-N-methylpyridin-2-amine3-{5-[1-(3-chlorophenyl)-2-(4-methylphenyl)ethyl]- 78.31,2,4-oxadiazol-3-yl}-N-methylpyridin-2-amine3-{5-[2-(3,4-dimethylphenyl)-1-(3-fluorophenyl)ethyl]- 35.71,2,4-oxadiazol-3-yl}-N-methylpyridin-2-amine3-{5-[2-(3,4-dimethylphenyl)-1-(3-methoxyphenyl)ethyl]- 77.61,2,4-oxadiazol-3-yl}-N-methylpyridin-2-amine3-{5-[1-(4-chlorophenyl)-2-phenylethyl]-1,2,4- 2400oxadiazol-3-yl}-N-methylpyridin-2-amineN-methyl-3-{5-[2-(4-methylphenyl)-1-(2- 928thienyl)ethyl]-1,2,4-oxadiazol-3-yl}pyridin-2-amine3-{5-[1-(5-chloropyridin-3-yl)-2-(3,4-dimethylphenyl)ethyl]- 14.51,2,4-oxadiazol-3-yl}-N-methylpyridin-2-amine3-{5-[1-(3,5-difluorophenyl)-2-(3,4-dimethylphenyl)ethyl]- 121,2,4-oxadiazol-3-yl}-N-methylpyridin-2-amine

1. A compound having Formula I, its enantiomers, diastereoisomers,tautomers or a pharmaceutically acceptable salt thereof,

wherein: A is a 5- or 6-membered ring heterocycle; B is C₆ aryl, C₃₋₈cycloalkyl; R¹ is H, halogen, —OC₁₋₈ alkyl, C₁₋₈ alkyl, CN, C(O)R¹¹,NO₂, NR¹²R¹³ or hydroxyl; R² is H, halogen, —OC₁₋₈ alkyl, C₁₋₈ alkyl,CN, C(O)R¹¹, NO₂, NR¹²R¹³ or hydroxyl; R³ is H, halogen, —OC₁₋₈ alkyl,C₁₋₈ alkyl, CN, C(O)R¹¹, NO₂, NR¹²R¹³ or hydroxyl; R⁴ is H, halogen,—OC₁₋₆ alkyl, C₁₋₈ alkyl, CN, C(O)R¹¹, NR¹²R¹³ or hydroxyl; R⁵ is H,halogen, —OC₁₋₈ alkyl, C₁₋₈ alkyl, CN, C(O)R¹¹, NR¹²R¹³ or hydroxyl; R⁶is H, halogen, —OC₁₋₈ alkyl, C₁₋₈ alkyl, CN, C(O)R¹¹, NR¹²R¹³ orhydroxyl; R⁷ is H, halogen, —OC₁₋₈ alkyl, C₁₋₈ alkyl, CN, C(O)R¹¹,NR¹²R¹³ or hydroxyl; R⁸ is H, halogen, —OC₁₋₈ alkyl, C₁₋₈ alkyl, CN,C(O)R¹¹, NR¹²R¹³ or hydroxyl; L is CH₂; R¹¹ is H or C₁₋₆ alkyl; R¹² is Hor C₁₋₆ alkyl; R¹³ is H or C₁₋₆ alkyl; R¹⁴ is H, C₁₋₆ alkyl or C₃₋₆cycloalkyl; and R¹⁵ is H, C₁₋₆ alkyl or C₃₋₆ cycloalkyl.
 2. A compoundaccording to claim 1, wherein:


3. A compound according to claim 1, wherein: R¹ is H, halogen, —OC₁₋₆alkyl, C₁₋₆ alkyl or NO₂; R² is H, halogen, —OC₁₋₆ alkyl, C₁₋₆ alkyl orNO₂; R³ is H, halogen, —OC₁₋₆ alkyl, C₁₋₆ alkyl or NO₂; R⁴ is H, halogenor C₁₋₆ alkyl, R⁵ is H, halogen or C₁₋₆ alkyl; R⁶ is H, halogen or —C₁₋₆alkyl; L is CH₂; R⁷ is H, halogen or C₁₋₆ alkyl; and R⁸ is H, halogen or—C₁₋₆ alkyl. R¹⁴ is H, C₁₋₆ alkyl or C₃₋₆ cycloalkyl; and R¹⁵ is H, C₁₋₆alkyl or C₃₋₆ cycloalkyl.
 4. A compound according to claim 1, wherein:

R¹ is H, halogen, —OC₁₋₆ alkyl, C₁₋₆ alkyl or NO₂; R² is H, halogen,—OC₁₋₆ alkyl, C₁₋₆ alkyl or NO₂; R³ is H, halogen, —OC₁₋₆ alkyl, C₁₋₆alkyl or NO₂; R⁴ is H, halogen or C₁₋₆ alkyl, R⁵ is H, halogen or C₁₋₆alkyl; R⁶ is H, halogen or —C₁₋₆ alkyl; L is CH₂; R⁷ is H, halogen orC₁₋₆ alkyl; and R⁸ is H, halogen or —C₁₋₆ alkyl. R¹⁴ is H, C₁₋₆ alkyl orC₃₋₆ cycloalkyl; and R¹⁵ is H, C₁₋₆ alkyl or C₃₋₆ cycloalkyl.
 5. Acompound according to claim 4, wherein: R¹ is H, chloro, bromo, fluoro,methyl, ethyl, methoxy or —NO₂; R² is H, chloro, trifluoromethyl, methylor methoxy; R³ is H, fluoro or methyl; R⁴ is H or methyl; R⁵ is H,methyl, chloro or iso-butyl; R⁶ is H, methyl or chloro; R⁷ is H; and R⁸is H.
 6. A compound according to claim 1, selected from:3-{5-[1-(5-chloropyridin-3-yl)-2-(3,4-dimethylphenyl)ethyl]-1,2,4-oxadiazol-3-yl}-N-methylpyridin-2-amine;3-{5-[1-(6-chloropyridin-3-yl)-2-(3,4-dimethylphenyl)ethyl]-1,2,4-oxadiazol-3-yl}-N-methylpyridin-2-amine;3-{5-[1-(6-chloropyridin-3-yl)-2-(3,5-dimethylphenyl)ethyl]-1,2,4-oxadiazol-3-yl}-N-methylpyridin-2-amine;N-methyl-3-(5-(1-(thiophen-3-yl)-2-(p-tolyl)ethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-amine;3-(5-(2-(3,4-dimethylphenyl)-1-(thiophen-3-yl)ethyl)-1,2,4-oxadiazol-3-yl)-N-methylpyridin-2-amine;N-methyl-3-(5-(1-(thiophen-2-yl)-2-(p-tolyl)ethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-amine;and3-(5-(2-(3,4-dimethylphenyl)-1-(thiophen-2-yl)ethyl)-1,2,4-oxadiazol-3-yl)-N-methylpyridin-2-amine.7. A pharmaceutical composition comprising as active ingredient atherapeutically effective amount of a compound according to claim 1, anda pharmaceutically acceptable adjuvant, diluents or carrier.
 8. Apharmaceutical composition according to claim 7, wherein the compound isselected from:3-{5-[1-(5-chloropyridin-3-yl)-2-(3,4-dimethylphenyl)ethyl]-1,2,4-oxadiazol-3-yl}-N-methylpyridin-2-amine;3-{5-[1-(6-chloropyridin-3-yl)-2-(3,4-dimethylphenyl)ethyl]-1,2,4-oxadiazol-3-yl}-N-methylpyridin-2-amine;3-{5-[1-(6-chloropyridin-3-yl)-2-(3,5-dimethylphenyl)ethyl]-1,2,4-oxadiazol-3-yl}-N-methylpyridin-2-amine;N-methyl-3-(5-(1-(thiophen-3-yl)-2-(p-tolyl)ethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-amine;3-(5-(2-(3,4-dimethylphenyl)-1-(thiophen-3-yl)ethyl)-1,2,4-oxadiazol-3-yl)-N-methylpyridin-2-amine;N-methyl-3-(5-(1-(thiophen-2-yl)-2-(p-tolyl)ethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-amine;and3-(5-(2-(3,4-dimethylphenyl)-1-(thiophen-2-yl)ethyl)-1,2,4-oxadiazol-3-yl)-N-methylpyridin-2-amine.9.-11. (canceled)